Intraperitoneal drug delivery offers a promising strategy for localized treatment of peritoneal tumours and post-surgical wound care. To control drug release profiles, drugs are often embedded within peritoneal implants or delivery devices. Typically, release studies from these devices are performed in phosphate-buffered saline (PBS), which underestimates in vivo release due to its lower drug solubility compared to human peritoneal fluid (hPF). Adding surfactants or albumin alone does not replicate the complexity of hPF, and few studies have addressed the development of a simulated peritoneal fluid (sPF). Accordingly, this study aimed to develop a biorelevant sPF based on hPF composition and to evaluate its ability to mimic hPF. The developed formulation contained salts, glucose, albumin, phosphatidylcholine stabilized by cholesterol and surfactants. The physicochemical properties (pH, buffering capacity, osmolality, wettability, and flow) of the formed fluid were assessed alongside conducting solubility studies of five model drugs with diverse ionization status (acids, bases, and neutral species) in sPF, hPF, and PBS. The results demonstrated that PBS underperformed relative to hPF, while sPF closely matched hPF in buffering capacity, osmolality, flow behaviour, solubilization of the model drugs, and wetting ability. These findings support the use of sPF as a biorelevant medium for solubility and release studies of intraperitoneal drug delivery systems.